4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide commonly known as Regorafenib. Regorafenib is marketed under the brand name Stivarga by Bayer Healthcare. It is approved in United States as Regorafenib monohydrate on 27 Sep. 2012. Regorafenib is indicated for the treatment of patients with metastatic colorectal cancer (CRC).
U.S. Pat. No. 7,351,834 B1 generically discloses Regorafenib, a pharmaceutically acceptable salt thereof, but there is no specific disclosure of Regorafenib in said patent or its equivalents. The patent discloses a process for the preparation of desfluoro analog of Regorafenib i.e. Sorafenib, involving the reaction of 4-chloro-3-(trifluoromethyl)phenyl isocyanate with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline in dichloromethane.
U.S. Pat. No. 8,637,553 B2 A1 specifically discloses Regorafenib, pharmaceutically acceptable salts thereof and its composition thereof. Also discloses the process for the preparation of Regorafenib by reacting 4-(4-amino-3-fluorophenoxy) pyridine-2-carboxylic acid methylamide in toluene with 4-chloro-3-(trifluoromethyl) phenyl isocyanate. The reaction mass was concentrated under reduced pressure and the residue was triturated with diethyl ether. The resulting solid was collected by filtration and dried to afford Regorafenib.
WO 2005/009961 disclosed Regorafenib and its process for the preparation. The monohydrate of said compound is disclosed in WO 08/043446.
WO 2005/009961 is also disclosed polymorph-I of Regorafenib, US2010/0113533A1 disclosed the polymorph-II of Regorafenib and US2010/0063112A1 disclosed polymorph-III of Regorafenib and process for the preparation thereof.
Polymorphism is the occurrence of different solid state forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids having the same molecular formula and different physical properties such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with desired solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction and by other methods such as, infrared spectrometry and differential scanning calorimetry. Solvent medium and mode of crystallization play very important role in obtaining a polymorphic form over the other.
Most of the prior reported processes for the preparation of Regorafenib compound of formula-1 provide Regorafenib with higher level of impurities which are toxic in nature. Especially, 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula-4 remains as impurity in, the final API. Further it requires number of purifications to reduce or remove the said impurity.
In view of the above, there is a need in the art to develop a process for the preparation of Regorafenib compound of formula-1 which controls the level of above said genotoxic impurities and enhances the purity of the desired compound thereby useful for the pharmaceutical composition.
The present inventors have developed a process for the preparation of Regorafenib and surprisingly got Regorafenib with desired purity by simple modifications.
The present invention relates to a process for the preparation of crystalline polymorph-I of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl]amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide compound of formula-1 through its DMSO solvate of compound of formula-1 which controls the level of genotoxic impurities thereby meets the desired ICH quality.
The present invention also relates to an amorphous form of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl]amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide and its process.